Active substances commonly delivered by inhalation include bronchodilators such as beta-2 adrenoreceptor agonists and anticholinergics, corticosteroids, anti-allergics and other active ingredients that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
Formoterol, i.e. 2′-hydroxy-5′-[(RS)-1-hydroxy-2 {[(RS)-p-methoxy-α-methylphenethyl]amino} ethyl] formanilide, particularly its fumarate salt (hereinafter indicated as FF), is a well known beta-2 adrenergic receptor agonist, currently used clinically in the treatment of bronchial asthma, chronic obstructive pulmonary disease (COPD) and related disorders.
Beclometasone dipropionate (BDP) is a potent anti-inflammatory steroid, named (8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-1′-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate, available under a wide number of brands for the prophylaxis and/or treatment of inflammatory respiratory disorders.
A formulation for pressurized metered dose inhalers (pMDIs) containing both active ingredients in combination, both dissolved in a mixture of HFA134a and ethanol as co-solvent is currently on the market. It has been quoted in the literature as FF/BDP extra-fine formulation.
Said formulation provides a high lung deposition and uniform distribution throughout the bronchial tree, and is characterized by the fact that is capable of delivering a high fraction of particles having a diameter equal or less than 1.1 micron. In particular, upon actuation of the inhaler, it gives rise to a respirable fraction of about 40% and a fraction of particles having a diameter equal or less than 1.1 micron of about 12% for both active ingredients.
The major advantage of said formulation is related to the improved penetration into the bronchiole-alveolar distal part of the respiratory tree wherein inflammation is known to play a role in spontaneous exacerbations of asthma symptoms and wherein it is known that the density of the beta-2 adrenergic receptors is particularly high.
However, despite their popularity, pMDI formulation may have some disadvantages in particular in elderly and pediatric patients, mostly due to their difficulty to synchronize actuation from the device with inspiration.
Dry powder inhalers (DPIs) constitute a valid alternative to MDIs for the administration of drugs to airways.
On the other hand, drugs intended for inhalation as dry powders should be used in the form of micronised particles. Their volumetric contribution could represent an obstacle to design a formulation therapeutically equivalent to one wherein the drugs are delivered in form of liquid droplets.
WO 01/78693 discloses a dry powder formulation comprising formoterol and BDP in combination as active ingredient and, as a carrier, a fraction of coarse particles and a fraction made of fine excipient particles and magnesium stearate.
Upon its actuation, the respirable fraction of BDP is about 40%, while that of formoterol is about 47%.
More recently Mariotti et al (European Respiratory Society Annual Congress held in Amsterdam on Sep. 24-28, 2011), presented data about a FF/BDP dry powder formulation having a respirable fraction of about 70% for both active ingredients.
It is therefore an object of the invention to provide a powder formulation for DPIs comprising formoterol fumarate and BDP in combination, overcoming the problems indicated above and in particular to provide a powder formulation having therapeutic characteristics matching those of the corresponding pMDI formulation in form of solution.
The problem is solved by the formulation of the present invention.